The role of C-peptide in the attenuation of outcomes of diabetic kidney disease: a systematic review and meta-analysis

Oliveira, Camila Marques; Domingueti, Caroline Pereira

doi:10.1590/2175-8239-JBN-2017-0027

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Brazilian Journal of Nephrology

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Review Articles • J. Bras. Nefrol. 40 (4) • Oct-Dec 2018 • https://doi.org/10.1590/2175-8239-JBN-2017-0027 copy

The role of C-peptide in the attenuation of outcomes of diabetic kidney disease: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Introduction:

Preclinical trials have shown that C-peptide may contribute to the treatment of diabetic kidney disease (DKD). This systematic review and meta-analysis aimed to assess the use of C-peptide in attenuating the outcomes of DKD.

Methods:

Searches were made on databases PubMed, Web of Science, and Scielo for in vivo clinical and preclinical trials written in English, Portuguese or Spanish that looked into the use of C-peptide in the attenuation of the outcomes of DKD.

Results:

Twelve papers were included in this review, one clinical and eleven preclinical trials. In the clinical trial, DKD patients given C-peptide had lower levels of albuminuria than the subjects in the control group, but glomerular filtration rates were not significantly different. The main parameters assessed in the preclinical trials were glomerular filtration rate (six trials) and albuminuria (five trials); three trials described less hyperfiltration and three reported lower levels of albuminuria in the groups offered C-peptide. The meta-analysis revealed that the animals given C-peptide had lower glomerular volumes and lower urine potassium levels than the groups not given C-peptide.

Conclusion:

The results of the studies included in the systematic review diverged. However, the meta-analysis showed that the animals given C-peptide had lower glomerular volumes and lower urine potassium levels.

Keywords:
C-peptide; Diabetic Nephropathy; Diabetes Mellitus

Author/Year	Rodent strain/time of exposure to diabetes	Method to induce DM	Type of C-peptide administered	Dose of C-peptide administered/route/site and time of administration	Size of the case and control groups	Assessed parameters
Xuet al., 2015⁵5 Xu S, Jiang Y, Wang H, Wang Z, Liu H, Peng L, et al. C-peptide ameliorates renal injury in type 2 diabetic rats through protein kinase A-mediated inhibition of fibronectin synthesis. Biochem Biophys Res Commun 2015;458:674-80.	Goto-Gakizaki rats/10 weeks	Fat-rich diet for two weeks	Rat C-peptide	50 pmol/kg/min of C-peptide administered subcutaneously for 12 weeks through a micropump implanted in the abdominal cavity	Group with DM given C-peptide = 8; group with DM not given C-peptide = 8	Albuminuria, fibronectin synthesis expression
Nakamoto et al., 2015¹⁵15 Nakamoto H, Nakayama K, Emoto N, Kajiya F. The short-term effects of C-peptide on the early diabetes-related ultrastructural changes to the podocyte slit diaphragm of glomeruli in rats. Microcirculation 2015;22:122-32.	Wistar rats/17 to 18 weeks	Streptozotocin 50 mg/kg	Not reported	50 pmol/kg/min of C-peptide administered subcutaneously for 24 hours with a micropump implanted on the back of the rats	Group with DM given C-peptide = 20; group with DM not given C-peptide = 11	Space between podocyte foot processes
Sunet al., 2010¹⁶16 Sun W, Gao X, Zhao X, Cui D, Xia Q. Beneficial effects of C-peptide on renal morphology in diabetic rats. Acta Biochim Biophys Sin (Shanghai) 2010;42:893-9.	Sprague-Dawley rats/2 weeks	Intravenous injection of streptozotocin 50 mg/kg	Human C-peptide	130 nmol/kg of C-peptide injected subcutaneously twice a day for 8 weeks	Group with DM given C-peptide = 9; group with DM not given C-peptide = 9	Kidney-to-body weight ratio, glomerular volume, ratio of the extracellular matrix area to the whole glomerular area
Kamikawa et al., 2008¹⁷17 Kamikawa A, Ishii T, Shimada K, Makondo K, Inanami O, Sakane N, et al. Proinsulin C-peptide abrogates type-1 diabetes-induced increase of renal endothelial nitric oxide synthase in rats. Diabetes Metab Res Rev 2008;24:331-8.	Sprague-Dawley rats/1 week	Intraperitoneal injection of streptozotocin 45 mg/kg	Human C-peptide	35 pmol/min/kg of C-peptide administered subcutaneously for a week through an osmotic pump	Group with DM given C-peptide = 7; group with DM not given C-peptide = 11	Expression of eNOS in the kidneys and glomerular volume
Nordquist et al., 2007¹⁸18 Nordquist L, Moe E, Sjöquist M. The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats. Diabetes Metab Res Rev 2007;23:400-5.	Sprague-Dawley rats/2 weeks	Intravenous injection of streptozotocin 55 mg/kg	Rat C-peptide and C-peptide fragment	50 pmol/kg/min of C-peptide and 500 pmol/kg/min of C-peptide fragment administered for 100 minutes	Group with DM given C-peptide = 9; Group with DM given C-peptide fragment = 9; group with DM not given C-peptide = 8	GFR calculated based on inulin clearance, urinary flow rate, urine sodium and potassium
Rebsomen et al., 2006¹⁹19 Rebsomen L, Pitel S, Boubred F, Buffat C, Feuerstein JM, Raccah D, et al. C-peptide replacement improves weight gain and renal function in diabetic rats. Diabetes Metab 2006;32:223-8.	Sprague-Dawley rats/1 week	Intraperitoneal injection of streptozotocin 65 mg/kg	Rat C-peptide	50 pmol/kg/dia of C-peptide administered for 28 days by continuous intraperitoneal infusion with an osmotic minipump placed in the peritoneal cavity	Group with DM given C-peptide = 6; group with DM not given C-peptide = 6	Proteinuria, urine sodium, and GFR calculated based on creatinine clearance
Maezawa et al., 2006⁸8 Maezawa Y, Yokote K, Sonezaki K, Fujimoto M, Kobayashi K, Kawamura H, et al. Influence of C-peptide on early glomerular changes in diabetic mice. Diabetes Metab Res Rev 2006;22:313-22.	C57/Bl6J mice/2 weeks	Intraperitoneal injection of streptozotocin 100 mg/kg	Rat C-peptide and modified C-peptide	290 pmol/kg/min of C-peptide administered subcutaneously for 24 hours or a week with an osmotic pump	Group with DM given C-peptide = 7; group with DM given modified C-peptide = 7; group with DM not given C-peptide = 7	Albuminuria, expression of collagen IV and TFG-β, and GFR calculated based on creatinine clearance
Samnegard et al., 2005²⁰20 Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Ekberg K, Isaksson B, et al. C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant 2005;20:532-8.	Wistar rats/4 weeks	Intravenous injection of streptozotocin 60 mg/kg	Rat C-peptide	50 pmol/kg/min of C-peptide administered for four weeks by continuous intraperitoneal infusion with an osmotic pump placed on the neck	Group with DM given C-peptide = 11; group with DM not given C-peptide = 11	Glomerular volume, mesangial volume, mesangial matrix volume, albuminuria, urine potassium and sodium, GFR calculated based on inulin clearance, and glomerular basement membrane thickening
Samnegard et al., 2004²¹21 Samnegård B, Jacobson SH, Johansson BL, Ekberg K, Isaksson B, Wahren J, et al. C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 2004;19:1385-91.	Sprague-Dawley rats/2 weeks	Intravenous injection of streptozotocin 55 mg/kg	Rat C-peptide	50 pmol/kg/min of C-peptide administered for 60 minutes	Group with DM given C-peptide = 13; group with DM not given C-peptide = 7	GFR calculated based on inulin clearance
Huang et al., 2002²²22 Huang DY, Richter K, Breidenbach A, Vallon V. Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol 2002;365:67-73.	Sprague-Dawley rats/2 weeks	Administration of streptozotocin 65 mg/kg	Human C-peptide	Intravenous bolus injection of 0,6; 1.8; 6; 18 and 60 nmol/kg followed by continuous infusion of 30 nmol/kg/h of C-peptide	Group with DM given C-peptide = 11 (dose 0.1x); 10 (dose 0.3x); 7 (dose 1x); 9 (dose 3x); 8 (dose 10x); group with DM not given C-peptide = 14	Albuminuria and serum calcium and sodium levels
Samnegard et al., 2001⁹9 Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Sjöquist M. Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Kidney Int 2001;60:1258-65.	Sprague-Dawley rats/2 weeks	Intravenous injection of streptozotocin 60 mg/kg	Rat C-peptide	50 pmol/kg/min of C-peptide administered for 2 weeks by continuous intravenous infusion with an osmotic pump placed in the subcutaneous tissue of the neck connected to a catheter inserted in the right jugular vein of the rats	Group with DM given C-peptide = 7; group with DM not given C-peptide = 7	Glomerular volume, GFR calculated based on inulin clearance, albuminuria, and urine sodium and potassium

Author/Year	Outcomes
Xu et al., 2015⁵5 Xu S, Jiang Y, Wang H, Wang Z, Liu H, Peng L, et al. C-peptide ameliorates renal injury in type 2 diabetic rats through protein kinase A-mediated inhibition of fibronectin synthesis. Biochem Biophys Res Commun 2015;458:674-80.	Group given C-peptide had lower albuminuria (p < 0.01) and fibronectin expression (p < 0.01) than controls.
Nakamoto et al., 2015¹⁵15 Nakamoto H, Nakayama K, Emoto N, Kajiya F. The short-term effects of C-peptide on the early diabetes-related ultrastructural changes to the podocyte slit diaphragm of glomeruli in rats. Microcirculation 2015;22:122-32.	Group given C-peptide had wider spaces between podocyte foot processes than controls (p < 0.05).
Sun et al., 2010¹⁶16 Sun W, Gao X, Zhao X, Cui D, Xia Q. Beneficial effects of C-peptide on renal morphology in diabetic rats. Acta Biochim Biophys Sin (Shanghai) 2010;42:893-9.	Group given C-peptide had lower kidney-to-body weight ratio (p < 0.05), lower glomerular volume (p < 0.01), and lower ratio of the extracellular matrix area to the whole glomerular area (p < 0.01) than controls.
Kamikawa et al., 2008¹⁷17 Kamikawa A, Ishii T, Shimada K, Makondo K, Inanami O, Sakane N, et al. Proinsulin C-peptide abrogates type-1 diabetes-induced increase of renal endothelial nitric oxide synthase in rats. Diabetes Metab Res Rev 2008;24:331-8.	Group given C-peptide had lower kidney eNOS expression than controls (p < 0.05); no significant differences were seen between the group given C-peptide and controls in terms of glomerular volume.
Nordquist et al., 2007¹⁸18 Nordquist L, Moe E, Sjöquist M. The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats. Diabetes Metab Res Rev 2007;23:400-5.	Group given C-peptide and C-peptide fragment had less hyperfiltration than controls (p < 0.05); no significant differences were seen between the groups given C-peptide or C-peptide fragment and controls in relation to urinary flow rate and urine sodium and potassium.
Rebsomen et al., 2006¹⁹19 Rebsomen L, Pitel S, Boubred F, Buffat C, Feuerstein JM, Raccah D, et al. C-peptide replacement improves weight gain and renal function in diabetic rats. Diabetes Metab 2006;32:223-8.	Group given C-peptide had lower proteinuria and urine sodium than controls (p < 0.05); no significant differences were seen between the group given C-peptide and controls in regards to GFR.
Maezawaet al., 2006⁸8 Maezawa Y, Yokote K, Sonezaki K, Fujimoto M, Kobayashi K, Kawamura H, et al. Influence of C-peptide on early glomerular changes in diabetic mice. Diabetes Metab Res Rev 2006;22:313-22.	Group given C-peptide had lower albuminuria (p < 0.01) and expression of collagen IV and TGF-β (p < 0.05) than controls; no significant differences were seen between the group given modified C-peptide and controls in regards to albuminuria and expression of collagen IV and TGF-β; no significant differences were seen between the groups in terms of GFR.
Samnegard et al., 2005²⁰20 Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Ekberg K, Isaksson B, et al. C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant 2005;20:532-8.	Group given C-peptide had lower glomerular volume (p < 0,001), lower mesangial volume (p < 0.01), and lower mesangial matrix volume (p < 0.01) than controls; no significant differences were seen between the group given C-peptide and controls in regards to albuminuria, urine sodium and potassium, GFR, and thickening of the glomerular basement membrane.
Samnegard et al., 2004²¹21 Samnegård B, Jacobson SH, Johansson BL, Ekberg K, Isaksson B, Wahren J, et al. C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 2004;19:1385-91.	Group given C-peptide had less hyperfiltration than controls.
Huang et al., 2002²²22 Huang DY, Richter K, Breidenbach A, Vallon V. Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol 2002;365:67-73.	No significant differences were seen between the group given C-peptide and controls in regards to albuminuria and serum sodium and potassium levels.
Samnegard et al., 2001⁹9 Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Sjöquist M. Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Kidney Int 2001;60:1258-65.	Group given C-peptide had lower glomerular volume, less hyperfiltration (p < 0.001) and albuminuria than controls; no significant differences were seen between the group given C-peptide and controls in regards to urine sodium and potassium.

Author/Year	Selection bias			Performance bias		Detection bias		Attrition bias	Reporting bias	Other sources of bias
Author/Year	1	2	3	4	5	6	7	8	9	10
Xu et al., 2015⁵5 Xu S, Jiang Y, Wang H, Wang Z, Liu H, Peng L, et al. C-peptide ameliorates renal injury in type 2 diabetic rats through protein kinase A-mediated inhibition of fibronectin synthesis. Biochem Biophys Res Commun 2015;458:674-80.	S	Y	?	Y	?	?	?	Y	Y	Y
Nakamoto et al., 2015¹⁵15 Nakamoto H, Nakayama K, Emoto N, Kajiya F. The short-term effects of C-peptide on the early diabetes-related ultrastructural changes to the podocyte slit diaphragm of glomeruli in rats. Microcirculation 2015;22:122-32.	Y	Y	?	Y	?	?	?	Y	Y	Y
Sun et al., 2010¹⁶16 Sun W, Gao X, Zhao X, Cui D, Xia Q. Beneficial effects of C-peptide on renal morphology in diabetic rats. Acta Biochim Biophys Sin (Shanghai) 2010;42:893-9.	Y	Y	?	Y	?	?	?	Y	Y	Y
Kamikawa et al., 2008¹⁷	Y	Y	?	Y	?	?	?	N	Y	Y
Nordquist et al., 2007¹⁸18 Nordquist L, Moe E, Sjöquist M. The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats. Diabetes Metab Res Rev 2007;23:400-5.	Y	Y	?	Y	?	?	?	Y	Y	Y
Rebsomen et al., 2006¹⁹19 Rebsomen L, Pitel S, Boubred F, Buffat C, Feuerstein JM, Raccah D, et al. C-peptide replacement improves weight gain and renal function in diabetic rats. Diabetes Metab 2006;32:223-8.	Y	Y	?	Y	?	?	?	Y	Y	Y
Maezawa et al., 2006⁸8 Maezawa Y, Yokote K, Sonezaki K, Fujimoto M, Kobayashi K, Kawamura H, et al. Influence of C-peptide on early glomerular changes in diabetic mice. Diabetes Metab Res Rev 2006;22:313-22.	Y	Y	?	Y	?	?	?	Y	Y	Y
Samnegard et al., 2005²⁰20 Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Ekberg K, Isaksson B, et al. C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant 2005;20:532-8.	Y	Y	?	Y	?	?	?	Y	Y	Y
Samnegard et al., 2004²¹21 Samnegård B, Jacobson SH, Johansson BL, Ekberg K, Isaksson B, Wahren J, et al. C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 2004;19:1385-91.	Y	Y	?	Y	?	?	?	Y	Y	Y
Huang et al., 2002²²22 Huang DY, Richter K, Breidenbach A, Vallon V. Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol 2002;365:67-73.	Y	Y	?	Y	?	?	?	Y	Y	Y
Samnegard et al., 2001⁹9 Samnegård B, Jacobson SH, Jaremko G, Johansson BL, Sjöquist M. Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Kidney Int 2001;60:1258-65.	Y	Y	?	Y	?	?	?	Y	Y	Y

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[1] Correspondence to: Caroline Domingueti E-mail: caroldomingueti@ufsj.edu.br